The present invention relates to a biodegradable copolymer useful in biomedical applications, including use as a tissue filler, a tissue adhesive, a bio-medical scaffold, and for the controlled delivery of pharmacological agents.
Biodegradable polymers are well known within the art as carriers for biologically active materials. Such biologically active materials may include therapeutic agents such as drugs, antibiotics, enzymes, and hormones. Further, polymers which form hydrogels can be used as carriers for cell suspensions and to increase the functional life of a carried material or agent. Copolymers can have an extensive range of permeability, pore sizes, and degradation rates which may be tailored for individual applications involving surgery, medical diagnosis, treatment, and research needs. Biodegradable synthetic polymers have evolved extensively since the first polylactic acid polymer was reported by Kulkierni et al 1966 xe2x80x9cPolylactic Acid for Surgical Implants,xe2x80x9d ARC Surg 93:839. Polyesters of lactic acid and glycolic acid have been widely used as biodegradable materials for drug delivery systems as set forth in U.S. Pat. No. 4,741,337 to Smith et al which is incorporated herein by reference. Frequently, the matrix of biodegradable polymers is hydrophobic in nature. Containment within such a matrix may result in certain enzymes and hydrophilic materials being present in an inactive conformation or undergoing an irreversible denaturation as a result of contact with solvents used in dispersing the carrier molecules within the polymer. While it has been suggested that rapidly degrading polymers may be used for short-term drug release, such use raises concerns of complications from acidic degradation by-products. Further, many biodegradable synthetic polymers require processing using organic solvents which present additional potential hazards. Accordingly, there remains room for improvement and variation within the art of synthetic biodegradable polymers.
Disclosed herein is a biocompatible, biodegradable, copolymer containing both hydrophobic and hydrophilic macromers. The resulting copolymer has a variety of uses in vivo. The copolymer has a water-soluble component in the form of an OH-containing polysaccharide such as dextran. An additional component of the copolymer is made from a hydrophilic polymer such as polylactide. In accordance with one aspect of this invention, it has been found that the macromers may be co-polymerized to form a copolymer having new and useful properties.
It is yet another aspect of this invention to provide a copolymer comprising a mixture of a polylactic acid which is co-polymerized with dextran. In one aspect of the present invention, the dextran has, prior to incorporation into the copolymer, been covalently bonded to a therapeutic agent such as a drug, hormone, or other useful molecule. The resulting copolymers are particularly useful for controlled drug delivery especially for use with a hydrophilic material, since the water-soluble region of the polymer may enable access of water to materials which may be embedded within the polymer matrix.
In yet another aspect of the invention, it is possible to incorporate materials which are entrapped in a non-covalent manner within the copolymer. Such materials may be introduced during the polymerization stage and offer an ability to provide two different release mechanisms of one or more biologically useful additives. For instance, release of non-covalently bound materials may occur by diffusion of the material from the copolymer prior to copolymer degradation or may result from release of the copolymer matrix as the polymer degrades. The release of entrapped materials may be regulated in part by the molecular weight of the various macromers and the cross-link density.
It is yet another aspect of the invention to provide a biodegradable copolymer in which the degraded constituents result in the formation of lactic acid and a polysaccharide such as glucose.
Certain aspects of the invention are provided by a copolymer in the form of a biocompatible, biodegradable, copolymer comprising a first backbone molecule of PLA bonded via a cross-linking reaction to a second backbone molecule of dextran wherein the dextran provides multiple hydroxyl functionalities.
An additional aspect of the invention is provided by a process of delivering a therapeutic agent to a patient comprising the steps of providing a first polymer of PLA; providing a second polymer of a polysaccharide; covalently bonding at least one therapeutic agent to the second polymer; cross linking the first polymer to the second polymer, thereby forming a copolymer; introducing the copolymer to a patient; releasing within the patient the at least one therapeutic agent from the second copolymer; degrading a portion of said PLA into lactic acid; and, releasing said lactic acid from the copolymer along a hydrophilic channel of the copolymer defined by the polysaccharide, thereby, slowing the degradation rate of the remaining portion of the PLA.
These and other features, aspects, and advantages of the present invention will become better understood with reference to the following description and appended claims.